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Rheumatology 1999; 38: 747-750
© 1999 British Society for Rheumatology

Paediatric Rheumatology: Autologous Stem Cell Transplantation in Rheumatic Diseases of Childhood

Side-effects of long-term immunosuppression versus morbidity in autologous stem cell rescue: striking the balance

Series Editor: P. Woo

D. Niethammer, J. Kümmerle-Deschner and G. E. Dannecker

Department of Paediatrics, University of Tübingen, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany

Correspondence to: D. Niethammer, Department of Paediatrics, University of Tübingen, Hoppe-Seyler-Strasse 1, D-72076 Tübingen, Germany.

Prolonged, long-term immunosuppression is the state-of-the-art therapy for many autoimmune diseases, as more specific treatment options are still unavailable. Immunosuppressive therapy is especially problematic in children, particularly when the drug regimen contains steroids or higher doses of methotrexate (MTX) for a long period of time. Recent observations in stem cell-transplanted adult patients, indicating that signs of severe autoimmune disease disappeared for certain time periods or vanished completely [1–6], suggested that high-dose chemotherapy with autologous stem cell rescue could also be a successful treatment option for severe autoimmune disease in children. The question which remains to be answered at present is whether the possible benefit of this procedure is not outweighed by its morbidity and mortality.

The present paper does not actually compare short-term vs long-term immunosuppression, but long-term treatment in both instances which is terminated in one case by intensive short-term chemotherapy, as currently no child would enter a high-dose regimen at the beginning of the disease. Therefore, the intensive chemotherapy is given only after previously long-term treatment, possibly adding new problems to already existing ones, but offering the chance that the activity of the disease can be stopped for a certain time or even that cure can be achieved.

Immunosuppression usually signifies a non-specific inhibition of all or many immune responses. Of course, one would prefer a more specific inhibition of a few defined steps of the immune response, or, as a final goal, immunoregulation by antigen-specific inhibition. The development of tolerance against self, i.e. against antigens which are the possible targets of an autoimmune process, is a naturally occurring regulatory pathway resulting in antigen-specific inhibition [7]. Furthermore, particular infectious diseases such as HIV, Epstein–Barr virus, cytomegalovirus or measles can induce a more or less specific immunosuppression [8–10]. This is also true for certain drugs such as MTX, steroids, azathioprine, cyclosporin A or cyclophosphamide. However, although these drugs have been used for decades, knowledge about the mechanisms of action induced by these immunosuppressive substances is still incomplete.

For example, steroids penetrate a cell through its membrane and bind to a steroid receptor. The newly formed complex enters the nucleus where it binds to an upstream regulatory element, thus inhibiting ~1% of all genes [11]. The resulting known effects on the immune system are summarized in Table 1Go.


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  		TABLE 1.  Effects of steroids on the immune system
 
The mechanisms of MTX action have been studied since its discovery at the end of the 1940s [12, 13]. This folate antagonist is known to inhibit nucleotide synthesis, resulting in an antiproliferative effect which is used in oncology, especially for the treatment of acute lymphoblastic leukaemia. The dosage of MTX for the treatment of autoimmune disease is much lower than for the treatment of cancer, and the mechanisms of action for this low dosage remain unclear. Azathioprine also inhibits DNA synthesis by competing with inosine monophosphate. This drug is used in doses which are high enough to reduce the proliferation of lymphocytes, the production of immunoglobulins, some monocyte functions and cytokine production. Probably, MTX as well as azathioprine downregulate the chemotactic activity of leucocytes. Cyclophosphamide also inhibits DNA synthesis, but its specific mode of action in autoimmune disease remains to be determined. In contrast to MTX, it also acts on mitotically inactive cells and can induce profound bone marrow suppression in higher doses, followed without doubt by strong immunosuppression. A more specific immunoregulating drug is cyclosporin A, which inhibits the upregulation of the interleukin-2 gene induced by T-cell activation, but again the effects on T cells, B cells and granulocytes are numerous [14] (Table 2Go). In summary, there are multiple mechanisms of the immune function which can be inhibited by immunosuppressive drugs, such as antigen processing and presentation, activation, proliferation and adherence of cells, chemotaxis and apoptosis, or the production of cytokines and prostaglandins.


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  		TABLE 2.  Effects of cyclosporin A on the immune system
 
All immunosuppressive drugs have a non-specific and extremely heterogeneous mechanism of action, but their main consequences and side-effects are infections and malignancies. The frequency and intensity of these side-effects depend on the kind of drug, the time and dosage of its use, and the underlying disease. With or without intensive short-term treatment, all the above factors are heterogeneous and the various side-effects can be additive. The infection rate during long-term use of MTX has been shown to vary between 0 and 27% (Table 3Go). Most infections occur during the first year of treatment, which is also true for azathioprine. However, the rare opportunistic infections are a specific side-effect of MTX and they are not limited to any time period of treatment [15, 16]. Steroids can also increase the risk of infection and have many other well-known side-effects which are not summarized here, the most cumbersome probably being growth inhibition and severe osteoporosis.


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  		TABLE 3.  MTX and infection rate. Review of 27 studies; in a survey with 1942 patients and 3598 patient-years, the infection rate varied from 0 to 27%
 
Even more complicated is the aspect of induction of malignancy by long-term use of MTX. There is not much experimental evidence for this serious side-effect and it is generally accepted that MTX is non-oncogenic. It is still discussed controversially whether MTX induces cancer in arthritis patients or whether this disease is itself associated with a higher incidence of cancer [17]. There have been reports about the development of malignant lymphomas [16–18], which have, however, resolved spontaneously in many patients after withdrawal of MTX. In summary, it is safe to say that MTX is a superb drug for the treatment of autoimmune diseases, and although there is an increased risk for infections or possibly malignancies, the risk is small when compared to the clinical benefit. This situation is somewhat different for cyclophosphamide which is strongly associated with the development of malignancies, especially lymphoma, leukaemia and skin cancer. The relative risk of cancer is 1.5 times higher in treated patients than in the normal population [19] (Table 4Go).


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  		TABLE 4.  Cyclophosphamide (CYC) and rate of malignancy. Alkylating agents are strongly associated with the development of malignancy, especially lymphoma, leukaemia and skin cancer
 
Are there new approaches to the treatment of juvenile chronic arthritis (JCA)? New and more specific immune response modifiers have been developed, with others to follow. Various aspects of this therapeutic option are summarized in Table 5Go, but therapy with these new immune response modifiers also poses many problems [20]. One molecule may have more than one biological function and inhibition of the inflammatory process might also inhibit another (more) important action. On the other hand, two different molecules may have a similar biological function, one of them blocking an important back-up system. Furthermore, the biological function studied in vitro might be irrelevant in vivo, and, of course, the mechanisms of the disease process itself are still incompletely understood. Finally, the costs of new immune response modifiers will be very high as compared to even the most expensive non-steroidal anti-inflammatory drug and second-line agents or even when compared to high-dose chemotherapy followed by stem cell rescue. Further additional problems of immune response modifiers have to be considered in children. Long-term effects are more important in the growing organism with an immune system which might not be fully mature. Therefore, data obtained in adults might not be readily transferable to children and all young patients who receive these new drugs have to be monitored over a long period of time.


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  		TABLE 5.  Immune response modification: possible new approaches to the treatment of JCA
 
Striking the balance when comparing the two procedures in question is a difficult task (Table 6Go). In order to make a decision, one has to consider carefully the risks of high-dose chemotherapy with autologous stem cell rescue. The acute risk of mortality in children due to toxicity or infection is ~1–2% in experienced centres. There is no risk of graft-vs-host disease as no allogeneic stem cells are used. The long-term side-effects are rare, especially when no irradiation is used, but they add to the late sequelae of the previous long-term immunosuppression. However, this procedure offers a definitive chance of long-term remission or even cure. In summary, the decision between short-and long-term treatment could therefore be made as follows.


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  		TABLE 6.  Striking the balance: high-dose chemotherapy with autologous stem cell rescue vs long-term immunosuppression
 
  • If the disease activity is low or responds well to long-term immunosuppression with no obligation to use steroids, there is no reason for this intensive treatment.
  • If, however, the activity of the disease is high or the disease is frequently relapsing in spite of adequate therapy, especially when steroids (>0.3 mg/kg/day) are necessary over long periods of time, or when the disease is steroid dependent resulting in cessation of growth and other side-effects, treatment of the child with intensive short-term therapy could be recommended. Even when a remission is only obtained for 1 or 2 yr, the child will have time to recover from the side-effects and show catch-up growth.

The future has to show whether children will benefit from this new therapeutic approach. It is the duty of all involved paediatricians to determine the value of this promising regimen, especially when there is no other feasible way. Only by daring new treatment options can anything be gained in favour of children suffering from severe autoimmune diseases. This lesson had to be learned in paediatric oncology many years ago. At that time, paediatric oncologists encountered a lot of aggression from many of their colleagues for this way of thinking, but today nobody can doubt that this approach was very successful. In contrast to malignant diseases, severe autoimmune diseases in children are normally not lethal, but there are data showing that many of these patients do not have a normal life expectancy. Many of the children not responding well to conventional therapy will suffer from severe side-effects and they might be handicapped for the rest of their life. Therefore, like in paediatric oncology many years ago, one is obliged to attempt this recently available approach for the treatment of these children.

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Accepted 15 March 1999


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